Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Variant: NM_000527.5(LDLR):c.1088C>A (p.Thr363Asn)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA10585297

251656 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: 0db2ea0d-bf45-4747-b92c-b460cbc3ca36

Approved on: 2025-03-24

Published on: 2025-03-24

HGVS expressions

NM_000527.5:c.1088C>A

NM_000527.5(LDLR):c.1088C>A (p.Thr363Asn)

NC_000019.10:g.11111541C>A

CM000681.2:g.11111541C>A

NC_000019.9:g.11222217C>A

CM000681.1:g.11222217C>A

NC_000019.8:g.11083217C>A

NG_009060.1:g.27161C>A

ENST00000252444.10:c.1346C>A

ENST00000559340.2:c.1088C>A

ENST00000560467.2:c.968C>A

ENST00000558518.6:c.1088C>A

ENST00000252444.9:c.1342C>A

ENST00000455727.6:c.584C>A

ENST00000535915.5:c.965C>A

ENST00000545707.5:c.707C>A

ENST00000557933.5:c.1088C>A

ENST00000558013.5:c.1088C>A

ENST00000558518.5:c.1088C>A

ENST00000560173.1:n.87C>A

ENST00000560467.1:c.568C>A

NM_000527.4:c.1088C>A

NM_001195798.1:c.1088C>A

NM_001195799.1:c.965C>A

NM_001195800.1:c.584C>A

NM_001195803.1:c.707C>A

NM_001195798.2:c.1088C>A

NM_001195799.2:c.965C>A

NM_001195800.2:c.584C>A

NM_001195803.2:c.707C>A

Uncertain Significance

BP4 PP4 BS3_Supporting PM2

PS4 PS3 PS1 PP1 PP3 PM5 BA1 BS2 BS4 BS1

Evidence Links 0

Expert Panel

Familial Hypercholesterolemia VCEP

Criteria Specification Information

Criteria Specification: ClinGen Familial Hypercholesterolemia Expert Panel Specifications to the ACMG/AMP Variant Classification Guidelines Version 1.2

PDF

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Familial Hypercholesterolemia VCEP

The NM_000527.5(LDLR):c.1088C>A (p.Thr363Asn) variant is classified as Uncertain significance - conflicting evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, PP4, BS3_Supporting and BP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 24 March 2025. The supporting evidence is as follows: PM2: This variant is absent from gnomAD (gnomAD v4.1.0). BP4: REVEL=0.345, it is below 0.50, splicing evaluation required. Functional data on splicing is not available. A) not on limits, B) does not create AG, C) there are two AG nearby: First AG -- MES score: variant cryptic site= 1.75, wt cryptic site= 2.69, canonical WT site=13.90. Ratio Var cryptic/Wt cryptic= 1.75/2.69=0.65 --- not above 1.1. Ratio Var cryptic/Wt canonical=1.75/13.90=0.92 --- it is above 0.9. Second AG -- MES score: variant cryptic site= -5.84, wt cryptic site= -3.45, canonical WT site=13.90. Variant not predicted to alter splicing. BS3_Supporting: Level 3 assay, PMID 37719435 (Graça et al., 2023): Heterologous cells (CHO), microscopy assays. Result: 90-100% LDLR expression and 95-98% LDLR activity. Functional study is consistent with no damaging effect. PP4: Variant meets PM2 and is identified in 1 case with Possible FH by Simon Broome criteria from Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge, Portugal, after alternative causes of high cholesterol were excluded.

BP4

REVEL=0.345, it is below 0.50, Splicing evaluation required. Functional data on splicing is not available. A) not on limits, B) does not create AG, C) there are two AG nearby: First AG -- MES score: variant cryptic site= 1.75, wt cryptic site= 2.69, canonical WT site=13.90. Ratio Var cryptic/Wt cryptic= 1.75/2.69=0.65 --- not above 1.1. Ratio Var cryptic/Wt canonical=1.75/13.90=0.92 --- it is above 0.9. Second AG -- MES score: variant cryptic site= -5.84, wt cryptic site= -3.45, canonical WT site=13.90. Variant not predicted to alter splicing.

PP4

Variant meets PM2 and Identified in 1 FH case from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge with Simon Broome Possible, after alternative causes of high cholesterol were excluded.

BS3_Supporting

Level 3 assays, PMID 37719435: . Heterologous cells (CHO), microscopy assays . Result: 90-100% LDLR expression and 95-98% LDLR activity Functional study is consistent with no damaging effect.

PM2

This variant is absent from gnomAD (gnomAD v4.1.0)

PS4

Variant identified in only 1 FH case

PS3

Level 3 assays, PMID 37719435: . Heterologous cells (CHO), microscopy assays . Result: 90-100% LDLR expression and 95-98% LDLR activity Functional study is consistent with no damaging effect.

PS1

1 other missense variants in the same codon: - NM_000527.5(LDLR):c.1088C>T (p.Thr363Ile) (ClinVar ID 1967129) - Uncertain Significance by these guidelines There are no variants in the same codon classified as Pathogenic by these guidelines.

PP1

Variant segregates with FH phenotype in only 1 informative meiosis.

PP3

REVEL=0.345, it is below 0.50, Splicing evaluation required. Functional data on splicing is not available. A) Not on limits B) Does not create AG C) there are two AG nearby: First AG: variant cryptic site= 1.75, wt cryptic site= 2.69, canonical WT site=13.90 Ratio Var cryptic/Wt cryptic= 1.75/2.69=0.65 => not above 1.1 Ratio Var cryptic/Wt canonical=1.75/13.90=0.92 => it is above 0.9 Second AG: variant cryptic site= -5.84, wt cryptic site= -3.45, canonical WT site=13.90 Ratio Var cryptic/Wt cryptic= -5.84/-3.45= 1.69 => above 1.1 Ratio Var cryptic/Wt canonical= -5.84/13.90=0.42 => not above 0.9 Variant not predicted to alter splicing

PM5

BA1

This variant is absent from gnomAD (gnomAD v4.1.0)

BS2

Variant was not identified in controls.

BS4

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

BS1

This variant is absent from gnomAD (gnomAD v4.1.0)

Curation History

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